Clinical outcomes and impact of therapeutic intervention in patients with acute myeloid leukemia who experience <scp>measurable residual disease</scp> (MRD) recurrence following <scp>MRD</scp>‐negative remission
Authors: Nicholas J. Short, Walid Macaron, Tapan Kadia, Courtney Dinardo, Ghayas C. Issa, Naval Daver, Sa Wang, Jeff Jorgensen, Daniel Nguyen, Aram Bidikian, Keyur P. Patel, Sanam Loghavi, Marina Konopleva, Musa Yilmaz, Elias Jabbour, Abhishek Maiti, Hussein A. Abbas, Elizabeth Shpall, Uday Popat, Gheath Al‐Atrash, Sherry Pierce, Hagop M. Kantarjian, Farhad Ravandi
Journal: American Journal of Hematology (2022)

Recurrence of MRD in AML is associated with imminent relapse unless intervened upon. Change in chemotherapy regimen and/or immediate transplant improve outcomes. In patients with acute myeloid leukemia (AML) who achieve complete remission (CR) with frontline therapy, the cure rate is only 40%–50%, highlighting that many patients harbor persistent residual disease that predisposes to relapse.1 Measurable residual disease (MRD) refers to neoplastic cells that are detectable in patients with morphological remission using techniques that are more sensitive than conventional cytomorphological assessment.2, 3 Persistent MRD after leukemia-directed therapy is one of the most powerful prognostic factors in AML, and achievement of MRD negativity is associated with a nearly two-third reduction in the risk of relapse or death.4 While several studies have evaluated the dynamics of MRD clearance and their association with clinical outcomes in the frontline setting, to our knowledge, no study has systematically evaluated the prognostic impact of MRD recurrence in patients with AML after initial achievement of an MRD-negative remission. An understanding of the outcomes of patients with AML who experience MRD recurrence would not only inform prognostication for these patients but could also guide therapeutic decision-making. However, the ability to intervene with MRD-directed therapy in patients with MRD recurrence is dependent on the latency period between MRD detection and overt relapse, which is largely unknown. To address these questions, we conducted a retrospective study to evaluate the prognostic impact of MRD recurrence in patients with non-core-binding factor AML in first remission. Eligible patients received frontline AML therapy at our institution, achieved CR or CR with incomplete hematologic recovery as the best response, and achieved MRD negativity by multiparameter flow cytometry (MFC) in first remission. MRD recurrence was only evaluated in patients who were in the first continuous remission without allogeneic stem cell transplantation (allo-SCT). MRD assessment was performed on fresh bone marrow aspiration samples using 8-color MFC as described previously.5 The sensitivity of this assay is 0.1% or better. All specimens with unequivocally positive results were included in this analysis. However, specimens with indeterminate MRD assessment or with negative results but suboptimal cell counts were excluded. MRD recurrence was defined as newly detectable MRD by MFC at any level in a patient who previously had at least one high-quality MRD-negative bone marrow assessment. Morphological relapse was defined as a recurrence of bone marrow blasts >5% or extramedullary AML. The flow chart of the study population is shown in Figure 1A. Among 740 patients with AML who achieved an MRD-negative first remission at our institution between August 2011 and July 2021, 55 patients (7.4% of all MRD-negative patients) experienced an MRD recurrence while in first remission. The baseline characteristics of patients with MRD recurrence are shown in Table S1. The median time between first documentation of MRD-negative remission and MRD recurrence was 6.0 months (range, 1.4–53.3 months). At the time of MRD recurrence, 44 patients (80%) were on active therapy and 11 (20%) had completed frontline therapy and were on observation (4 after intensive chemotherapy and 7 after lower-intensity therapy). In 45 patients (82%), recurrent MRD was detected during routine surveillance, and in 10 (18%), the evaluation was prompted by a clinical concern. The median level of MRD at the time of recurrence was 0.7% (range, 0.05%–4.0%). The median time to morphological relapse among patients with MRD recurrence was 5.9 months, and the estimated 1-, 2-, and 5-year cumulative incidence of relapse (CIR) were 68%, 82%, and 82%, respectively (Figure S1). Notably, the risk of relapse was particularly high in the first 6 months, and by 3 months, 42% of patients had already relapsed. The median relapse-free survival (RFS) after MRD recurrence was 5.5 months, and the 1-, 2-, and 5-year RFS rates were 29%, 16%, and 6%, respectively (Figure 1B). The median overall survival (OS) was 18.1 months, and the 1-, 2-, and 5-year OS rates were 59%, 43%, and 22%, respectively (Figure 1C). Patients with adverse-risk cytogenetics had a significantly inferior median RFS compared with those with a non-adverse risk karyotype (2.8 vs. 8.7 months; p = 0.006; Figure S2A); median OS was also inferior for those with adverse-risk cytogenetics (7.9 months vs. 36.1 months; p < 0.001; Figure S2B). Similarly, the European LeukemiaNet 2017 cyto-molecular risk predicted outcomes after MRD recurrence. The median RFS for patients with an adverse, intermediate, and favorable risk of AML was 2.8, 7.7, and 16.5 months, respectively (p for trend = 0.03; Figure S2C), and the median OS for these patients was 10.8, 18.1, and 46.8 months, respectively (p for trend = 0.01; Figure S2D). OS was significantly higher for patients who received intensive chemotherapy versus lower-intensity therapy (median OS: 36.1 months vs. 15.3 months; p = 0.02; Figure S3). Duration from the last MRD-negative bone marrow to MRD recurrence did not impact either RFS or OS (Figure S4). There was no difference in the number of cycles required to achieve MRD negativity between those who relapsed after MRD recurrence and compared with those who relapsed without MRD recurrence. However, the median time between achievement of MRD negativity and morphological relapse was longer in patients with MRD recurrence than in those who relapsed without MRD recurrence (10.2 vs. 7.9 months; p = 0.08). Figure S5 shows the interventions performed at the time of MRD recurrence and patient disposition. Thirty-six patients (65%) continued with their current therapy at the time of MRD recurrence. Three of these patients eventually converted to MRD-negativity, 28 relapsed, and 5 remained in MRD-positive remission at last follow-up (3 of whom died in MRD-positive remission). Three patients (5%) received no therapy for MRD-positive disease, all of whom subsequently relapsed. Sixteen patients (29%) changed therapy at the time of MRD recurrence. Nine of these patients proceeded directly to allo-SCT, and 7 changed chemotherapy regimens (all with a hypomethylating agent-based regimen). Among the 9 patients who went directly to allo-SCT, all but one converted to MRD-negativity after allo-SCT. Among the 7 patients who changed chemotherapy regimens, 3 converted to MRD-negativity and 4 remained MRD-positive. Among the 16 patients who changed therapy at the time of MRD recurrence, the median time to therapeutic intervention was 1.1 months (range, 0.1–4.3 months). In a 1.1-month landmark analysis, patients who changed therapy or underwent allo-SCT at the time of MRD recurrence had significantly better RFS and OS than patients who continued their current therapy. The median RFS for intervention versus continuation of current therapy was 14.5 and 2.8 months, and the 5-year RFS rate was 31% and 5%, respectively (p = 0.01; Figure 1D); the median OS was 36.1 and 10.9 months, and the 5-year OS rate was 45% and 17%, respectively (p = 0.01; Figure 1E). There was no difference in outcomes between patients who proceeded directly to allo-SCT at the time of MRD recurrence and those who changed chemotherapy regimens (Figure S6). Among the 39 patients who either continued with current therapy or were monitored at the time of MRD recurrence, the 5-year CIR, RFS, and OS rates were 96%, 4%, and 15%, respectively. Overall, 12 patients underwent allo-SCT after MRD recurrence while still in first morphological remission (9 directly after MRD recurrence and 3 after receiving a new chemotherapy regimen). Among the 12 transplanted patients, the median RFS and OS were both 36.1 months, and the 5-year RFS and OS rates were 38% and 42%, respectively (Figure S7). In contrast, among the non-transplanted population, only one patient was alive and without relapse beyond 2 years. MRD is a powerful prognostic factor in patients with AML undergoing frontline therapy, with an estimated 5-year RFS and OS rates for MRD-positive patients of 25% and 34%, respectively, in a large meta-analysis.4 In our study, we specifically analyzed the outcomes of patients with MRD recurrence after initial MRD-negative remission and found that these patients had very poor outcomes, with estimated 5-year RFS and OS rates of 6% and 22%, respectively—rates that appear substantially worse than historical expectations of patients with MRD persistence, suggesting that MRD recurrence in AML is likely to represent a state of imminent relapse for many patients. We observed MRD recurrence in 55 patients (7.4% of all MRD-negative patients). The relatively small proportion of patients who were found to have MRD recurrence prior to relapse is likely due to the lack of frequent MRD monitoring—often every 3–6 months in clinical practice—and the rapid kinetics of relapse in many cases, particularly those with poor-risk cyto-molecular features. In our cohort, over 40% of patients relapsed within 3 months of MRD recurrence, indicating that very frequent MRD monitoring would be required to reliably identify MRD recurrence prior to morphological relapse. Current consensus recommendations do not provide specific guidance for the frequency of MRD assessments when MFC MRD is used.3 Our data suggest that MRD surveillance at least every 3 months for the first year after the first MRD-negative remission is likely required to reliably detect MRD recurrence. Our results also provide support for MRD-directed intervention in patients who experience MRD recurrence after initial MRD-negative remission. In a landmark analysis, patients who underwent a change in therapy (either directly to allo-SCT or change in chemotherapy, with or without subsequent allo-SCT) had superior RFS and OS, compared with those who continued the same treatment regimen. The 5-year RFS rate was 31% for this approach, suggesting that therapeutic intervention can lead to durable remissions in a substantial proportion of patients with MRD recurrence. In summary, we found that patients with AML who experience MRD recurrence after initial MRD-negative remission have very high rates of relapse and poor survival. Therapeutic intervention with a change of treatment regimen and/or allo-SCT may improve outcomes for these patients and can lead to durable remissions in some patients; in contrast, patients who continue the same therapy without allo-SCT almost universally relapse. These data suggest that frequent MRD monitoring should be performed in patients undergoing frontline AML therapy and may allow for early identification of patients with impending relapse who may benefit from MRD-directed strategies. Nicholas J. Short designed the study, collected and analyzed the data, treated patients, and wrote the manuscript. Walid Macaron designed the study, collected and analyzed the data, and wrote the manuscript. Sa Wang and Jeff Jorgensen conducted the MFC MRD analyses. Tapan Kadia, Courtney Dinardo, Naval Daver, Marina Konopleva, Ghayas C. Issa, Musa Yilmaz, Elias Jabbour, Abhishek Maiti, Elizabeth Shpall, Uday Popat, Gheath Al-Atrash, Hagop M. Kantarjian, and Farhad Ravandi treated patients. Daniel Nguyen, Aram Bidikian, and Sherry Pierce collected and analyzed the data. All authors critically reviewed and approved the manuscript. This study is supported by an MD Anderson Cancer Center Support Grant (CA016672). Nicholas J. Short is supported by the K12 Paul Calabresi Clinical Oncology Scholar Award and the American Society of Hematology Junior Faculty Scholar Award in Clinical Research. The authors declare no potential conflict of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. Appendix S1 Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.